RAPIDLY DISINTERGRATING COMPOSTIONS AND METHODS (Nicotine)

ABSTRACT

A rapidly infusing composition that includes (a) a pharmaceutically acceptable binder and/or excipient system containing gelatin and mannitol, and (b) active therapeutic ingredient (ATI). Preferred rapidly infusing compositions are those formulated with nicotine or a derivative/analog thereof as the ATI. A method of administering an ATI such as nicotine or a derivative/analog thereof, to a subject is also disclosed. The subject is administered the rapidly infusing composition via the oral mucosa, for example, to reduce the subject&#39;s usage of more harmful nicotine delivery methods and/or nicotine withdrawal symptoms.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. patent application Ser. No.17/225,738 filed Apr. 8, 2021, which claims priority to U.S. ProvisionalApplication No. 63/114,194 filed Nov. 16, 2020; U.S. ProvisionalApplication No. 63/114,181 filed Nov. 16, 2020; U.S. ProvisionalApplication No. 63/147,453 filed Feb. 9, 2021; U.S. ProvisionalApplication No. 63/172,343 filed Apr. 8, 2021; U.S. ProvisionalApplication No. 63/172,362 filed Apr. 8, 2021; U.S. ProvisionalApplication No. 63/172,386 filed Apr. 8, 2021; U.S. ProvisionalApplication No. 63/172,368 filed Apr. 8, 2021; and U.S. ProvisionalApplication No. 63/180,193 filed Apr. 27, 2021; which are eachincorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION Technical Field

The present disclosure relates to a rapidly infusing composition fororal mucosal uptake, in particular, for administration of nicotine.Specifically, rapidly infusing compositions formulated with nicotine ora derivative/analog thereof as the active therapeutic ingredient (ATI),useful as a nicotine substitute for reducing a subject's usage of moreharmful nicotine delivery methods and/or nicotine withdrawal symptoms.

Description of the Related Art

The “background” description provided herein is for the purpose ofgenerally presenting the context of the disclosure. Work of thepresently named inventors, to the extent it is described in thisbackground section, as well as aspects of the description which may nototherwise qualify as prior art at the time of filing, are neitherexpressly or impliedly admitted as prior art against the presentinvention.

Nicotine is the principal pharmacologically active component of tobacco.Users of tobacco products use them primarily for the experience theyreceive from nicotine, either in the form of tobacco smoke, chewingtobacco, or oral tobacco pouches. Smoking tobacco, such as withcigarettes, cigars, and pipes, is the most common method of consumingtobacco and adsorbing nicotine. However, smoking tobacco is associatedwith health hazards which are not necessarily related to theadministration of nicotine itself. For example, there are over 4,000toxic substances formed or released during the combustion of tobacco incigarettes, such as carcinogenic nitrosamines, carbon monoxide,acrolein, and tar products, many of which are carcinogenic or associatedwith other disease states such as cardiovascular and pulmonary diseases.

Despite these known health risks, it is difficult for tobacco users toquit smoking, as nicotine is a strongly addictive substance thatpresents user's with potent nicotine withdrawal symptoms such asanxiety, irritability, nausea, fatigue, depression, insomnia, etc. As aresult, there has been great interest in alternative means ofadministering nicotine without the toxic substances associated with thecombustion of tobacco, that satisfies a user's nicotine dependence tofacilitate reduction of or cessation from smoking.

Yet, nicotine replacement therapies often fail due to inadequatenicotine uptake and receptor saturation. Smoking a cigarette provides analmost immediate adsorption of nicotine into the smoker's blood whichquickly reaches the brain. Here, the peak levels of nicotine allowsbinding to the nicotinic acetylcholine receptors (nAChRs) at around 90%saturation (Brody A L, Mandelkern M A, London E D, et al. CigaretteSmoking Saturates Brain α4β2 Nicotinic Acetylcholine Receptors. Arch GenPsychiatry. 2006; 63(8):907-914—incorporated herein by reference in itsentirety) which activates these receptors to release dopamine, givingthe smoker rapid satisfaction. Nicotine also appears to induce therelease of endogenous opioids that activate opioid pathways in thereward system. These pharmacological actions are thought to be largelyresponsible for the strongly reinforcing effects of nicotine. The rapiddelivery of nicotine and near immediate satisfying of nicotine cravingsprovided by peak receptor saturation from smoking tobacco has provendifficult to emulate using other nicotine administration modes.

For example, nicotine gum, nicotine lozenges, nicotine transdermalpatches, as well as oral non-tobacco-based nicotine pouches (e.g., ZYN©products from Swedish Match or VELO™ products from Reynolds VaporCompany) are capable of providing a rather high steady state nicotineblood concentration, but they do not provide the rapid adsorption andpeak nicotine levels obtained from smoking tobacco. As a result ofnicotine release profiles being too slow, and in many cases nicotinerelease being incomplete (delivering only a fraction of the availablenicotine to the user), many smokers find such products to be lesssatisfying, and thus an unacceptable alternative to smoking tobacco.

In addition to providing immediate relief from nicotine cravings,successful therapies for smoking cessation should also reduce thebehavioral pattern associated with smoking (i.e., should be habitbreaking). Many nicotine replacement therapies, including tobacco-smokefree inhalers (e.g., electronic cigarettes), smokeless tobacco products(e.g., chewing tobacco, snuff, and snus), oral non-tobacco-basednicotine pouches (e.g., ZYN© products from Swedish Match or VELO™products from Reynolds Vapor Company), etc., are unsuccessful infacilitating the reduction of or cessation of nicotine product use,because these therapies replace one habit (i.e., smoking cigarettes)with another habit (e.g., smoking electronic cigarettes, dipping,snusing, etc.).

Further, many nicotine administration methods currently available tonicotine users are unhygienic, a problem exacerbated during the times ofCOVID-19 where personal hygiene and sanitation are under intensescrutiny. For example, smokeless tobacco products (e.g., chewingtobacco, snuff, and snus), oral non-tobacco-based nicotine pouches, andnicotine gums each require a user to remove spent tobacco matter,pouches, or wads of gum base from their mouth after completion.

SUMMARY OF THE INVENTION

In view of the forgoing, there exists a need for new nicotinereplacement therapies that do not advance or sustain behavioral habitssuch as those accompanying smoking tobacco, are sanitary and discreet,and that are capable of rapidly infusing nicotine into the user'sbloodstream at high peak levels for receptor saturation and immediaterelief of nicotine withdrawal symptoms.

Accordingly, it is an object of the present invention to provide novelrapidly infusing compositions formulated with nicotine or a suitablederivative/analog thereof that meet the above criteria.

It is another object of the present invention to provide novel processesfor manufacturing the rapidly infusing composition.

It is another object of the present invention to provide novel methodsof administering nicotine to a subject.

It is another object of the present invention to provide novel methodsof reducing a subject's usage of more harmful nicotine delivery methods.

It is another object of the present invention to provide novel methodsof reducing nicotine withdrawal symptoms in a subject.

It is another object of the present invention to provide novel methodsto increase the quiet enjoyment of administering nicotine in a subject.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discovery ofits Rapid Infusion Technology™ (RITe) platform through which nicotine orrelated derivatives/analogs can be administered via the oral mucosae,for rapid delivery of nicotine or a derivative/analog and immediaterelief of nicotine withdrawal symptoms, and doing so without advancingor sustaining a behavioral pattern.

Thus, the present invention provides:

(1) A rapidly infusing composition, comprising:

-   -   a pharmaceutically acceptable binder and/or excipient system        comprising gelatin and mannitol, and nicotine.

(2) The rapidly infusing composition of (1), which is lyophilized.

(3) The rapidly infusing composition of (1) or (2), which has adisintegration time of approximately 1 to 30 seconds in deionized watermaintained at 37° C.±2° C.

(4) The rapidly infusing composition of any one of (1) to (3), which hasa disintegration time of approximately 1 to 5 seconds in deionized watermaintained at 37° C. 2° C.

(5) The rapidly infusing composition of any one of (1) to (4), whereinthe gelatin is present in the rapidly infusing composition in an amountof 10 to 35 wt. %, based on a total weight of the rapidly infusingcomposition on a dry basis.

(6) The rapidly infusing composition of any one of (1) to (5), whereinthe gelatin is mammalian gelatin.

(7) The rapidly infusing composition of (6), wherein the mammaliangelatin is bovine gelatin.

(8) The rapidly infusing composition of any one of (1) to (7), whereinthe mannitol is present in the rapidly infusing composition in an amountof 5 to 35 wt. %, based on a total weight of the rapidly infusingcomposition on a dry basis.

(9) The rapidly infusing composition of any one of (1) to (8), whereinthe nicotine is present in the rapidly infusing composition in an amountof 0.1 to 25 wt. %, based on a total weight of the rapidly infusingcomposition on a dry basis.

(10) The rapidly infusing composition of any one of (1) to (9), whereinthe nicotine is provided in the form of a nicotine salt or a nicotinecomplex.

(11) The rapidly infusing composition of (10), wherein the nicotine isprovided in the form of the nicotine complex.

(12) The rapidly infusing composition of (10) or (11), wherein thenicotine complex is a nicotine cation exchange resin complex.

(13) The rapidly infusing composition of (12), wherein the nicotinecation exchange resin complex is nicotine polacrilex.

(14) The rapidly infusing composition of any one of (1) to (13), whereinthe nicotine has a purity between 95 and 100% by weight on a basis ofnicotine free base.

(15) The rapidly infusing composition of any one of (1) to (14), whichis formulated with a solid form of nicotine.

(16) The rapidly infusing composition of any one of (1) to (15), whereinthe rapidly infusing composition further comprises at least one selectedfrom the group consisting of a sweetener, a flavorant, and a colorant.

(17) The rapidly infusing composition of (16), wherein the rapidlyinfusing composition comprises the flavorant, and the flavorantcomprises a mixture of orange flavor and peppermint flavor.

(18) The rapidly infusing composition of (16) or (17), wherein therapidly infusing composition comprises the sweetener, and the sweetenercomprises a mixture of sucralose and acesulfame-K.

(19) A process for manufacturing the rapidly infusing composition of anyone of (1) to (18), comprising:

-   -   dissolving gelatin and mannitol in water to form a solution;    -   adding the nicotine to the solution to form a drug product        suspension; and    -   lyophilizing the drug product suspension to remove water and        form the rapidly infusing composition.

(20) A method of administering nicotine to a subject, comprisingadministering to the subject in need thereof, via the oral mucosa, atherapeutically effective amount of the rapidly infusing composition ofany one of (1) to (18).

(21) The method of (20), wherein the rapidly infusing composition isadministered buccally to the subject via the buccal mucosa.

(22) The method of (20) or (21), wherein the therapeutically effectiveamount of the rapidly infusing composition is that which provides from0.1 to 10 mg of nicotine per dose.

(23) The method of any one of (20) to (22), wherein the rapidly infusingcomposition is administered to the subject 1 to 10 times per day.

(24) The method of any one of (20) to (23), wherein the subject is ahuman.

(25) A method of reducing a subject's usage of more harmful nicotinedelivery methods, comprising administering to the subject in needthereof, via the oral mucosa, a therapeutically effective amount of therapidly infusing composition of any one of (1) to (18).

(26) The method of (25), wherein the rapidly infusing composition isadministered buccally to the subject via the buccal mucosa.

(27) The method of (25) or (26), wherein the therapeutically effectiveamount of the rapidly infusing composition is that which provides from0.1 to 10 mg of nicotine per dose.

(28) The method of any one of (25) to (27), wherein the rapidly infusingcomposition is administered to the subject 1 to 10 times per day.

(29) The method of any one of (25) to (28), wherein the subject is ahuman.

(30) A method of reducing nicotine withdrawal symptoms in a subject,comprising administering to the subject in need thereof, via the oralmucosa, a therapeutically effective amount of the rapidly infusingcomposition of any one of (1) to (18).

(31) The method of (30), wherein the rapidly infusing composition isadministered buccally to the subject via the buccal mucosa.

(32) The method of (30) or (31), wherein the therapeutically effectiveamount of the rapidly infusing composition is that which provides from0.1 to 10 mg of nicotine per dose.

(33) The method of any one of (30) to (32), wherein the rapidly infusingcomposition is administered to the subject 1 to 10 times per day.

(34) The method of any one of (30) to (33), wherein the subject is ahuman.

The foregoing paragraphs have been provided by way of generalintroduction, and are not intended to limit the scope of the followingclaims. The described embodiments, together with further advantages,will be best understood by reference to the following detaileddescription.

DETAILED DESCRIPTION OF THE INVENTION

In the following description, it is understood that other embodimentsmay be utilized and structural and operational changes may be madewithout departure from the scope of the present embodiments disclosedherein.

Definitions

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the disclosure. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be present,and all such stable isomers are contemplated in the present disclosure.Cis- and trans- (or E- and Z-) geometric isomers, when present, may beisolated as a mixture of isomers or as separated isomeric forms.Compounds referenced in the disclosure can be isolated in opticallyactive or racemic forms. Optically active forms may be prepared byresolution of racemic forms or by synthesis from optically activestarting materials. All processes used to prepare these compounds andintermediates made therein are considered to be part of the presentdisclosure. When enantiomeric or diastereomeric products are prepared,they may be separated by conventional methods, for example, bychromatography, fractional crystallization, or through the use of achiral agent. Depending on the process conditions, the end productsreferenced in the present disclosure are obtained either in free(neutral) or salt form. Both the free form and the salts of these endproducts are within the scope of the disclosure. If so desired, one formof a compound may be converted into another form. A free base or acidmay be converted into a salt; a salt may be converted into the freecompound or another salt; a mixture of isomeric compounds may beseparated into the individual isomers. Compounds referenced in thepresent disclosure, free form and salts thereof, may exist in multipletautomeric forms, in which hydrogen atoms are transposed to other partsof the molecules and the chemical bonds between the atoms of themolecules are consequently rearranged. It should be understood that alltautomeric forms, insofar as they may exist, are included within thedisclosure. Further, a given chemical formula or name shall encompassall conformers, rotamers, or conformational isomers thereof where suchisomers exist. Different conformations can have different energies, canusually interconvert, and are very rarely isolatable. There are somemolecules that can be isolated in several conformations. For example,atropisomers are isomers resulting from hindered rotation about singlebonds where the steric strain barrier to rotation is high enough toallow for the isolation of the conformers. It should be understood thatall conformers, rotamers, or conformational isomer forms, insofar asthey may exist, are included within the present disclosure.

As used herein, the term “solvate” refers to a physical association of areferenced compound with one or more solvent molecules, whether organicor inorganic. This physical association includes hydrogen bonding. Incertain instances, the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. Solvate encompassesboth solution phase and isolable solvates. Exemplary solvent moleculeswhich may form the solvate include, but are not limited to, water,methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol,tert-butanol, ethyl acetate and other lower alkanols, glycerin, acetone,dichloromethane (DCM), dimethyl sulfoxide (DMSO), dimethyl acetate(DMA), dimethylformamide (DMF), isopropyl ether, acetonitrile, toluene,N-methylpyrrolidone (NMP), tetrahydrofuran (THF), tetrahydropyran, othercyclic mono-, di- and tri-ethers, polyalkylene glycols (e.g.,polyethylene glycol, polypropylene glycol, propylene glycol), andmixtures thereof in suitable proportions. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates,isopropanolates and mixtures thereof. Methods of solvation are generallyknown to those of ordinary skill in the art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings without excessive toxicity, irritation,allergic response, or other problem or complication, commensurate with areasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salt” refers to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids and phenols. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,and nitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like. The pharmaceutically acceptable salts of thepresent disclosure can be synthesized from the parent compound thatcontains a basic or acidic moiety by conventional chemical methods.Generally, such salts can be prepared by reacting the free acid or baseforms of these compounds with a stoichiometric amount of the appropriatebase or acid in water or in an organic solvent, or in a mixture of thetwo; generally, non-aqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 18th Edition, MackPublishing Company, Easton, Pa. (1990)—which is incorporated herein byreference in its entirety.

When referencing a particular composition/material, the phrase “consistsessentially of”, means that the particular composition/material mayinclude minor amounts of impurities so long as those impurities do notaffect the basic and novel property of the invention—the ability toprovide immediate relief of nicotine withdrawal symptoms.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event(s) can or cannot occur or the subsequentlydescribed component(s) may or may not be present (e.g., 0 wt. %).

The terms “administer”, “administering”, “administration”, and the like,as used herein, refer to the methods that may be used to enable deliveryof the active therapeutic ingredient (ATI) to the desired site ofbiological action. Routes or modes of administration are as set forthherein. In this context, the terms “treat”, “treatment”, and the likerefers to the reduction or amelioration of severity of symptoms of thecondition being treated; reduction of duration of symptoms of thecondition being treated; reduction, inhibition, slowing, or arresting ofthe progression of symptoms associated with the condition; reduction offrequency of symptoms of the condition being treated; elimination ofsymptoms and/or underlying cause of the condition; prevention of theoccurrence of symptoms of the condition; and/or causing regression ofthe condition.

The term “subject” and “user” are used interchangeably. As used herein,they refer to any subject for whom or which administration or therapy isdesired. In most embodiments, the subject is a human.

The term “Rapid Infusion Technology™ (RITe) platform” or “rapidlyinfusing composition” as used herein means a solid dosage formcontaining medicinal substances that disintegrates rapidly in the oralcavity (when contacted with saliva) with no need for chewing ordrinking/swallowing liquids (e.g., water, liquid carriers, saliva, etc.)to ingest these medicinal substances, with an in-vitro disintegrationtime of 30 second or less according to the United States Pharmacopeia(USP) <701> Disintegration Test performed in deionized water maintainedat 37° C.±2°. The disclosed rapidly infusing compositions are thus adifferent dosage form than, for example, a chewable tablet, a lozengeintended to be dissolved slowly in the mouth, or a tablet that should beswallowed whole with food or liquid.

The dosage amount and treatment duration are dependent on factors, suchas bioavailability of a drug, administration mode, toxicity of a drug,gender, age, lifestyle, body weight, the use of other drugs and dietarysupplements, the disease stage, tolerance and resistance of the body tothe administered drug, etc., and then determined and adjustedaccordingly. The terms “effective amount”, “therapeutically effectiveamount”, or “therapeutically effective dose” refer to a sufficientamount of an active therapeutic ingredient (ATI) being administeredwhich provides the desired therapeutic or physiological effect oroutcome, for example, the amount of ATI sufficient for relieving to someextent one or more nicotine withdrawal symptoms associated with smokingcessation. The result can be a reduction and/or alleviation of the signsor symptoms of a condition, or any other desired alteration of abiological system. Undesirable effects, e.g. side effects, are sometimesmanifested along with the desired therapeutic effect; hence, apractitioner balances the potential benefits against the potential risksin determining what is an appropriate “effective amount”. The exactamount required will vary from subject to subject, depending on the ageand general condition of the subject, mode of administration, and thelike. An appropriate “effective amount” in any individual case may bedetermined by one of ordinary skill in the art using only routineexperimentation, for example through the use of dose escalation studies.

As used herein, “active” nicotine refers to nicotine free base.

As used herein, “more harmful nicotine delivery methods” refers tonicotine delivery methods using tobacco products-including tobaccocombustion products (e.g., cigarettes) and smokeless tobacco products(e.g., chewing tobacco, snuff, and snus)—as well as tobacco-smoke freeinhalers (e.g., electronic cigarettes).

Rapid Infusion Technology™ (RITe) Platform

The present disclosure provides a therapeutic formulation presented inthe form of a rapidly infusing composition which is suitable foradministration of active therapeutic ingredients (ATIs) such as nicotinevia a non-gastric mucosal surface. As described in more detail below,the novel RITe™ platform allows ATIs such as nicotine to be presented inunit dosage form for accurate dosing, rapid adsorption and onset oftherapeutic effect, and in an easy-to-take format that does not mimic,and hence reinforce, the repetitive actions associated with other moreharmful nicotine delivery methods. For example, the rapidly infusingcomposition may be presented in tablet form and packaged in individualblister units.

In particular, the RITe™ platform enables oral mucosal administration ofATIs in a solid dosage form directly into systemic circulation via thesublingual mucosa or the buccal mucosa. Administration may be carriedout by simply placing the rapidly infusing composition directly in thebuccal cavity (between the cheek and gum) or over the sublingual mucousgland (under the ventral surface of the tongue).

Preferred rapidly infusing compositions are those which are lyophilizedproducts formulated for rapid infusion when placed in such an oralenvironment for rapid release of the ATI. The rapidly infusingcompositions of the present disclosure may have a disintegration time offrom approximately 1 second to 30 seconds or less, preferably 25 secondsor less, preferably 20 seconds or less, preferably 15 seconds or less,preferably 10 seconds or less, preferably 5 seconds or less, preferably3 seconds or less, according to the United States Pharmacopeia (USP)<701> Disintegration Test performed in deionized water maintained at 37°C.±2°. In particular, preferred rapidly infusing compositions are thoseformulated for oral disintegration in 5 seconds or less, preferably 4seconds or less, preferably 3 seconds or less, preferably 2 seconds orless, preferably in approximately 1 second, according to the UnitedStates Pharmacopeia (USP) <701> Disintegration Test performed indeionized water maintained at 37° C.±2°. A disintegration profile nohigher than the above-mentioned upper limit provides a discrete amountof ATI to the user within a short time frame—a ‘bolus’ of ATI which israpidly absorbed through intimate contact with the oralmucosae-providing high peak serum levels of ATIs and short onset timesto therapeutic relief. For example, when formulated with nicotine as theATI, administration of the rapidly infusing composition disclosed hereinmay provide peak levels of nicotine sufficient to achieve binding to thenicotinic acetylcholine receptors (nAChRs) at 50% saturation or more,preferably 55% saturation or more, preferably 60% saturation or more,preferably 65% saturation or more, preferably 70% saturation or more,preferably 75% saturation or more, preferably 80% saturation or more,preferably 85% saturation or more, preferably 90% saturation or more,preferably 95% saturation or more, and up to 96% saturation, preferablyup to 97% saturation, preferably up to 98% saturation, preferably up to99% saturation.

As a result of the rapid disintegration profile, direct introduction ofthe ATI into systemic circulation through the sublingual mucosa or thebuccal mucosa, and ultimately high peak serum levels of ATI, the rapidlyinfusing compositions disclosed herein provide a rapid onset oftherapeutic effect. For example, the rapidly infusing compositionformulated with nicotine may provide the desired effect (e.g., relieffrom nicotine withdrawal symptoms), in under 15 minutes, preferablyunder 10 minutes, preferably under 5 minutes, preferably under 4minutes, preferably under 3 minutes, preferably under 2 minutes,preferably under 1 minute, preferably under 45 seconds, preferably under30 seconds, preferably under 20 seconds, preferably under 10 seconds,preferably approximately 5 seconds. Such short onset times arecomparable to those achieved through smoking tobacco, and are superiorto those which can be obtained with traditional nicotine replacementtherapies such as nicotine lozenges made through compression tabletting,gums, patches, nicotine oral pouches, and the like.

Another particular advantage of the disclosed rapidly infusingcompositions is that administration is not habit inducing. For example,unlike other routes for administering nicotine such as smoking, chewing,dipping, snusing, sucking, etc., all of which are designed to behabitually performed by the user over sustained periods of time, therapidly infusing compositions of the present disclosure are insteaddesigned to be placed in the buccal cavity or over the sublingual glandfor disintegration in a matter of seconds without mastication,deglutition, or any other neuromuscular activity. This “take it and it'sgone” administration route is not associated with a habit-formingactivity, which is particularly advantageous to those who desire tobreak a smoking habit.

Yet another particular advantage of the “take it and it's gone”administration of the rapidly infusing composition disclosed herein isthat administration is sanitary and discreet, with no need to remove aspent nicotine product from the mouth upon completion—a fundamental steprequired when using smokeless tobacco products (must remove spenttobacco mass or spent tobacco pouch), oral non-tobacco-based nicotinepouches (must remove spent nicotine pouch), and nicotine gums (mustremove spent wad of gum base). As a result, there may be lessembarrassment or stigma associated with the use of the rapidly infusingcompositions and increased quiet enjoyment of administering nicotine,which may be attractive to a wider user base, compared to other productssuch as nicotine pouches.

Yet another advantage of the RITe™ platform is that it enables effectivetaste masking of bitter-tasting ATIs such as nicotine. Two mainstrategies contribute to the taste masking success of the presentdisclosure. First, any issues related to bitter taste are fundamentallymitigated by the short oral residence times provided by the rapiddisintegration profile described heretofore. One “takes it and it'sgone.” Second, when formulated with a flavorant, a robust mixture offlavors will hit the tongue at essentially the same time—the bitterflavor of the ATI still hits the tongue, but the perception of theflavor is canceled or mitigated by the simultaneous arrival of otherflavors. Even then, the robust mixture of flavors will quickly subsideas the composition is rapidly absorbed through the oral mucosa.

The rapidly infusing composition also provides for reliable avoidance offirst pass metabolism owing to its rapid disintegration profile coupledto the direct introduction of the ATI into systemic circulation throughthe sublingual mucosa or the buccal mucosa. The short residence timespent in the oral cavity reduces the tendency for enteral oraladministration through voluntary or involuntary swallowing, and as aresult, high levels of bioavailability may be achieved. The rapidlyinfusing composition thus presents ATIs such as nicotine in a highlybioavailable dosage form for maximum therapeutic effects. For example,nicotine administered via the RITe™ platform herein may have abioavailability of at least 50%, preferably at least 55%, preferably atleast 60%, preferably at least 65%, preferably at least 70%, preferablyat least 75%, preferably at least 80%, preferably at least 85%,preferably at least 90%, and up to 99%, preferably up to 98%, preferablyup to 96%, preferably up to 95%, preferably up to 92%. Suchbioavailability is an improvement over other nicotine product types,with specific mention being made to nicotine gums, lozenges, andpouches, in part because considerable nicotine is swallowed withsubsequent first-pass metabolism owing to long oral residency timesusing such nicotine products.

The rapidly infusing composition herein generally contains (a) apharmaceutically acceptable binder and/or excipient system that includesgelatin and a sugar alcohol e.g., mannitol, and optionally one or moreof a sweetener, a flavorant, and a colorant; and (b) an activetherapeutic ingredient such as nicotine or a pharmaceutically acceptablederivative/analog or solvate thereof.

Pharmaceutically acceptable carrier and/or excipient system Carriersand/or excipients are ingredients which do not provide a therapeuticeffect themselves, but which are designed to interact with, and enhancethe properties of, the active therapeutic ingredient. In particular,carriers and/or excipients may act as a vehicle for transporting theactive therapeutic ingredient from one organ, or portion of the body, toanother organ, or portion of the body. The selection of appropriatecarrier/excipient ingredients may impact the solubility, distribution,release profile/kinetics, absorption, serum stability, therapeutic onsettime, and ultimately the efficacy of the ATI, as well as the shelf-life,dosage forms, and processability of the drug product. Each ingredient inthe pharmaceutically acceptable carrier and/or excipient system must be“pharmaceutically acceptable” in the sense of being compatible with theother ingredients of the rapidly infusing composition and not injuriousto the subject.

In light of the above, particular preference is given herein topharmaceutically acceptable carrier and/or excipient systems whichinclude gelatin and a sugar alcohol (e.g., mannitol).

Gelatin is to be included in the pharmaceutically acceptable carrierand/or excipient system in order to effect matrix formation in thelyophilized product, i.e., gelatin may act primarily as a matrix former.During manufacture of the rapidly infusing composition, lyophilizationfrom an aqueous suspension results in the removal of water therebyleaving behind a gelatin matrix/scaffolding upon which the ATI can beevenly dispersed or suspended. It has been found that gelatin has apropensity to establish a stable matrix in lyophilized form, yet allowfor rapid disintegration when brought into contact with the aqueous oralenvironment, thereby providing efficient transfer of the ATI from thehydrophilic vehicle to the oral mucosa. In this regard, mammaliangelatins such as bovine gelatin and porcine gelatin are preferred, withbovine gelatin being particularly preferred. In some embodiments, therapidly infusing composition does not contain fish gelatin.

The amount of gelatin used may be varied. Generally, gelatin may bepresent in the rapidly infusing composition in an amount of at least 10wt. %, preferably at least 12 wt. %, preferably at least 14 wt. %,preferably at least 16 wt. %, preferably at least 18 wt. %, preferablyat least 20 wt. %, preferably at least 22 wt. %, and up to 35 wt. %,preferably up to 32 wt. %, preferably up to 30 wt. %, preferably up to28 wt. %, preferably up to 26 wt. %, preferably up to 24 wt. %, based ona total weight of the rapidly infusing composition on a dry basis.

The pharmaceutically acceptable carrier and/or excipient system is alsoformulated with one or more sugar alcohols, which may act primarily as abulking agent. Examples of sugar alcohols include, but are not limitedto, erythritol, xylitol, sorbitol, maltitol, mannitol, lactitol, andglycerin, which may be used singly or in combinations. Advantage canalso be taken of the effect of certain sugar alcohols in terms of taste(sweetness and coolness due to endothermal heat of solution), as well astheir ability to aid/speed tablet disintegration. In this regard,particular preference is given to mannitol.

The sugar alcohol, preferably mannitol, may be present in the rapidlyinfusing composition in any amount which provides the desiredbulking/taste/disintegration effects. Generally, this amount will rangefrom at least 5 wt. %, preferably at least 10 wt. %, preferably at least12 wt. %, preferably at least 14 wt. %, preferably at least 16 wt. %,preferably at least 18 wt. %, and up to 35 wt. %, preferably up to 30wt. %, preferably up to 28 wt. %, preferably up to 26 wt. %, preferablyup to 24 wt. %, preferably up to 22 wt. %, preferably up to 20 wt. %,based on a total weight of the rapidly infusing composition on a drybasis.

In some embodiments, a weight ratio of gelatin to sugar alcohol rangesfrom 1:3, preferably from 1:2, preferably from 1:1, preferably from1.1:1, and up to 3:1, preferably up to 2:1, preferably up to 1.5:1,preferably up to 1.2:1.

The pharmaceutically acceptable carrier and/or excipient system may alsooptionally include one or more of a sweetener, a flavorant, and acolorant.

The sweetener may be used in any amount which provides the desiredsweetening effect, generally in amount of 0 to 10 wt. %, for example inan amount of up to 8 wt. %, preferably up to 6 wt. %, preferably up to 5wt. %, preferably up to 4.5 wt. %, preferably up to 4 wt. %, preferablyup to 3.5 wt. %, preferably up to 3 wt. %, preferably up to 2.5 wt. %,preferably up to 2 wt. %, preferably up to 1.5 wt. %, preferably up to 1wt. %, based on a total weight of the rapidly infusing composition on adry basis. Suitable examples of sweeteners include, but are not limitedto, aspartame, saccharin (as sodium, potassium or calcium saccharin),cyclamate (as a sodium, potassium or calcium salt), sucralose,acesulfame-K, thaumatin, neohisperidin, dihydrochalcone, ammoniatedglycyrrhizin, dextrose, maltodextrin, fructose, levulose, sucrose,glucose, isomalt, which may be used singly or in combinations, withparticular preference given to sucralose and acesulfame-K, morepreferably a mixture of sucralose and acesulfame-K.

It is to be readily appreciated by those of ordinary skill in the artthat one or more flavorants may be optionally included in the rapidlyinfusing composition to mask any unpleasant taste imparted by certainingredients (e.g., an unpleasant tasting ATI) or to otherwise impart anacceptable taste profile to the composition, and the composition is notlimited to any particular flavor. However, flavorants suitable with thepresent invention require trial and error in order to achieve desiredeffectiveness. Suitable flavorants include, but are not limited to, oilof wintergreen, oil of peppermint, oil of spearmint, oil of sassafras,oil of clove, cinnamon, anethole, menthol, thymol, eugenol, eucalyptol,lemon, lime, lemon-lime, orange, and other such flavor compounds to addfruit notes (e.g., citrus, cherry etc.), spice notes, etc., to thecomposition. The flavorants may be constitutionally composed ofaldehydes, ketones, esters, acids, alcohols (including both aliphaticand aromatic alcohols), as well as mixtures thereof. Specific mention ismade to orange flavor, peppermint flavor, or a mixture thereof, whichworks particularly well with nicotine as the ATI. The flavorant may beused in any amount which provides the desired flavor, generally in anamount of 0 to 10 wt. %, for example in an amount of up to 8 wt. %,preferably up to 6 wt. %, preferably up to 5 wt. %, preferably up to 4wt. %, preferably up to 3 wt. %, preferably up to 2 wt. %, preferably upto 1.5 wt. %, preferably up to 1 wt. %, preferably up to 0.5 wt. %,preferably up to 0.1 wt. %, based on a total weight of the rapidlyinfusing composition on a dry basis.

In some embodiments, the rapidly infusing compositions are formulatedwithout a flavorant. Such non-flavored rapidly infusing compositions maybe preferred in areas where sales of flavored nicotine products arebanned, or will be subject to bans in the future. Even in theseinstances, user compliance (e.g., in terms of temporary abstinence fromswallowing, which is often triggered when a subject is presented withfoul-tasting oral medications) with non-flavored rapidly infusingcompositions may be satisfactory, as any issues related to foul tasteare minimized with the short oral residence times provided by the rapiddisintegration profile described heretofore. However, the rapidlyinfusing compositions described here provide a safer alternative toother nicotine delivery methods such as e-cigarettes which are subjectto flavoring bans. Owing to improved safety, the rapidly infusingcompositions may be formulated with a variety of palatable flavorswithout similar restrictions.

Likewise, the rapidly infusing composition may be colored or tintedthrough the optional use of one or more colorants. Suitable colorantsare those approved by appropriate regulatory bodies such as the FDA andthose listed in the European Food and Pharmaceutical Directives andinclude both pigments and dyes such as FD&C and D&C dyes, with specificmention being made to FD&C Yellow #5 and FD&C Red #40, which togetherproduce an orange hue.

In addition to gelatin and a sugar alcohol (e.g., mannitol), andoptionally one or more of a sweetener, a flavorant, and a colorant, thepharmaceutically acceptable carrier and/or excipient system mayoptionally include one or more other pharmaceutically acceptablecarriers and/or excipients known to those of ordinary skill in art, inart appropriate levels. Examples of which include, but are not limitedto,

-   -   fillers or extenders such as starches (e.g., corn starch and        potato starch), sugars (e.g., lactose or milk sugar, maltose,        fructose, glucose, trehalose, sucrose), dextrates, dextrin,        polydextrose, high molecular weight polyethylene glycols,        silicic acid, aluminum monostearate, polyesters, polycarbonates,        and polyanhydrides;    -   binders, such as cellulose, and its derivatives, (e.g.,        carboxymethyl cellulose, sodium carboxymethyl cellulose,        hydroxypropyl cellulose, hydroxyethyl cellulose,        hydroxypropylmethyl cellulose, hydroxyethyl methyl cellulose,        methyl cellulose, ethyl cellulose, cellulose acetate, and        microcrystalline cellulose), alginates (e.g., sodium alginate),        polyvinyl pyrrolidone, powdered tragacanth, malt, acacia (gum        arabic), carbomer, carrageenan, chitosan, copovidone,        cyclodextrins, guar gum, inulin, pectin, polycarbophil or a salt        thereof, polyvinyl alcohol, pullulan, and xanthan gum;    -   disintegrating agents, such as agar-agar, calcium carbonate,        tapioca starch, alginic acid, certain silicates, sodium        carbonate, sodium starch glycolate, and cross-linked sodium        carboxymethyl cellulose;    -   surfactants/absorption accelerators/wetting agents/emulsifying        agents/solubilizers, including any of the anionic, cationic,        nonionic, zwitterionic, amphoteric and betaine variety, such as        polyalkylene oxide copolymers (e.g., poloxamer), sodium lauryl        sulfate, sodium dodecyl benzene sulfonate, sodium docusate,        sodium lauryl sulfoacetate, alkali metal or ammonium salts of        lauroyl sarcosinate, myristoyl sarcosinate, palmitoyl        sarcosinate, stearoyl sarcosinate and oleoyl sarcosinate, cetyl        alcohol, glycerol monostearate, polyoxyethylene sorbitol, fatty        acid esters of sorbitan, polysorbates (polyalkolyated fatty acid        esters of sorbitan) (e.g., polyoxyethylene sorbitan        monostearate, monoisostearate and monolaurate), polyethylene        oxide condensates of alkyl phenols, cocoamidopropyl betaine,        lauramidopropyl betaine, palmityl betaine, glyceryl monooleate,        glyceryl monostearate, fatty alcohols (e.g., cetostearyl and        cetyl alcohol), medium chain triglycerides, polyethoxylated        castor oil, polyethoxylated alkyl ethers (e.g., ethoxylated        isostearyl alcohols), polyethylene glycols (Macrogols),        polyoxyethylene stearates, anionic and nonionic emulsifying        waxes, propylene glycol, and propylene glycol alginates;    -   absorbents, such as kaolin and bentonite clay;    -   lubricants, such as talc, calcium stearate, magnesium stearate,        solid polyethylene glycols, zinc stearate, sodium stearate,        stearic acid, ethyl oleate, and ethyl laurate;    -   controlled release agents such as cross-linked polyvinyl        pyrrolidone (crospovidone);    -   opacifying agents such as titanium dioxide;    -   buffering agents, including alkaline buffering agents, such as        sodium hydroxide, sodium citrate, magnesium hydroxide, aluminum        hydroxide, sodium carbonate, sodium bicarbonate, potassium        phosphate, potassium carbonate, and potassium bicarbonate;    -   diluents/tableting agents such as dicalcium phosphate;    -   antioxidants, including (1) water soluble antioxidants, such as        ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium        metabisulfite, and sodium sulphite, (2) oil-soluble        antioxidants, such as ascorbyl palmitate, butylated        hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin,        propyl gallate, and alpha-tocopherol; and (3) metal chelating        agents, such as citric acid, ethylenediamine tetraacetic acid        (EDTA), tartaric acid, and phosphoric acid;    -   antibacterial and antifungal agents, such as paraben,        chlorobutanol, phenol, sorbic acid;    -   as well as other non-toxic compatible substances employed in        pharmaceutical formulations, such as liposomes, and micelle        forming agents;    -   including mixtures thereof.

Preferred rapidly infusing compositions are those which contain lessthan 1 wt. %, preferably less than 0.5 wt. %, preferably less than 0.1wt. %, preferably less than 0.05 wt. %, preferably less than 0.001 wt.%, preferably 0 wt. %, of other pharmaceutically acceptable carriersand/or excipients, such as those listed above, in particular bufferingagents and/or surfactants. In preferred embodiments, the rapidlyinfusing compositions are formulated without buffering agents,specifically alkaline buffering agents such as sodium hydroxide, sodiumcarbonate, sodium bicarbonate, potassium phosphate, potassium carbonate,and potassium bicarbonate, which are traditionally required for nicotineoral pouches, nicotine lozenges, or other compressed tablet forms (see,e.g., U.S. Pat. No. 8,940,772-incorporated herein by reference in itsentirety). In preferred embodiments, the rapidly infusing compositionsare formulated without surfactants/absorption accelerators/wettingagents/emulsifying agents/solubilizers. In preferred embodiments, therapidly infusing compositions are formulated without cellulose orderivatives thereof, such as microcrystalline cellulose.

Also preferred are rapidly infusing compositions which do not containinert diluents, aqueous carriers, or non-aqueous carriers commonly usedin the art for manufacture of liquid dosage forms for oraladministration, such as emulsions, microemulsions, solutions,suspensions, syrups, and elixirs. Examples of inert diluents, aqueous ornon-aqueous carriers, etc. which are preferably excluded herein mayinclude, but are not limited to, water or other solvents, solubilizingagents, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, glycerol,polyethylene glycol, propylene glycol, 1,3-butylene glycol, oils(whether synthetic, semi-synthetic, or naturally occurring, such as longchain triglycerides, mixed glycerides, and free fatty acids, inparticular, cottonseed oil, groundnut oil, corn oil, germ, olive oil,castor oil, sesame oil, borage oil, coconut oil, soybean oil, saffloweroil, sunflower oil, palm oil, peanut oil, peppermint oil, poppy seedoil, canola oil, hydrogenated soybean oil, hydrogenated vegetable oils,glyceryl distearate, behenic acid, caprylyic/capric glycerides, lauricacid, linoleic acid, linolenic acid, myristic acid, palmitic acid,palmitoleic acid, palmitostearic acid, ricinoleic acid, stearic acid,soy fatty acids, oleic acid, glyceryl esters of fatty acids such asglyceryl behenate, glyceryl isostearate, glyceryl laurate, glycerylpalmitate, glyceryl palmitostearate, glyceryl ricinoleate, glyceryloleate, glyceryl stearate), tetrahydrofuryl alcohol, fatty acid estersof sorbitan, organic esters such as ethyl oleate, and mixtures thereof,with specific mention being made to ethyl alcohol and sesame oil.

Active Therapeutic Ingredient (ATI)

The amount of active therapeutic ingredient (ATI) which can be combinedwith the pharmaceutically acceptable carrier and/or excipient system toproduce the rapidly infusing composition may vary depending upon thesubject, and other factors. The amount of ATI which can be combined withthe pharmaceutically acceptable carrier and/or excipient system toproduce a single dosage form will generally be that amount whichproduces a therapeutic effect (e.g., relief from nicotine withdrawalsymptoms). Generally, this amount will range from 0.1 to 25 wt. % of ATI(e.g., nicotine-active), for example, at least 0.1 wt. %, preferably atleast 0.5 wt. %, preferably at least 1 wt. %, preferably at least 2 wt.%, preferably at least 3 wt. %, preferably at least 4 wt. %, preferablyat least 5 wt. %, preferably at least 6 wt. %, preferably at least 7 wt.%, preferably at least 8 wt. %, preferably at least 9 wt. %, preferablyat least 10 wt. %, and up to 25 wt. %, preferably up to 24 wt. %,preferably up to 23 wt. %, preferably up to 22 wt. %, preferably up to21 wt. %, preferably up to 20 wt. %, preferably up to 19 wt. %,preferably up to 18 wt. %, preferably up to 17 wt. %, preferably up to16 wt. %, preferably up to 15 wt. %, preferably up to 14 wt. %,preferably up to 13 wt. %, preferably up to 12 wt. %, preferably up to11 wt. %, of the ATI, based on a total weight of the rapidly infusingcomposition on a dry basis.

In terms of unit dose, the rapidly infusing composition is generallyformulated with 0.1 to 10 mg of ATI per unit (e.g. tablet), for exampleat least 0.1 mg, preferably at least 0.2 mg, preferably at least 0.4 mg,preferably at least 0.6 mg, preferably at least 0.8 mg, preferably atleast 1 mg, preferably at least 1.2 mg, preferably at least 1.4 mg,preferably at least 1.6 mg, preferably at least 1.8 mg, preferably atleast 2 mg, and up to 10 mg, preferably up to 9 mg, preferably up to 8mg, preferably up to 7 mg, preferably up to 6.5 mg, preferably up to 6mg, preferably up to 5.5 mg, preferably up to 5 mg, preferably up to 4.5mg, preferably up to 4 mg of ATI per unit (e.g., tablet).

In preferred embodiments, the rapidly infusing composition is formulatedwith, as the active therapeutic ingredient, nicotine. When the rapidlyinfusing compositions are formulated with nicotine, the above weightpercentages and unit dosages are with respect to the active nicotinecontent (nicotine free base).

Nicotine useful herein may be synthetic nicotine or nicotine obtainedfrom natural sources (e.g., Nicotiana plant species such as Nicotianatabacum) that is unbound from plant material, i.e., naturally-occurringnicotine which is at least partially purified and not contained within aplant structure such as a tobacco leaf. Preferably, the rapidly infusingcomposition is formulated with nicotine that has been extracted andpurified from natural sources, such as nicotine extracted from aNicotiana species (e.g., tobacco). The nicotine can be purified bydistillation or other suitable methods known by those of ordinary skillin the art.

Whether synthetic or obtained from natural sources, the nicotine usedherein is preferably substantially pure or virtually pure, for example,having a purity of at least 95 wt. %, preferably at least 96 wt. %,preferably at least 97 wt. %, preferably at least 98 wt. %, preferablyat least 99 wt. %, and up to 99.1 wt. %, preferably up to 99.2 wt. %,preferably up to 99.3 wt. %, preferably up to 99.4 wt. %, preferably upto 99.5 wt. %, preferably up to 99.6 wt. %, preferably up to 99.7 wt. %,preferably up to 99.8 wt. %, preferably up to 99.9 wt. %, preferably upto 100 wt. %. The percent purity of nicotine refers to the percent ofnicotine by mass relative to a total weight of nicotine containingmaterial—the nicotine containing material being the sum of nicotine plusany additional impurities which may be present, such as those impuritiesoriginating from the biomass from which the nicotine is obtained (e.g.,Nicotiana species) or encountered during manufacture. Also, the nicotinepurity described herein is calculated by weight on a basis of nicotinefree base. Therefore, the purity of nicotine with respect to a nicotinesalt or a nicotine complex (vide infra) is determined on a basis ofnicotine free base, prior to salt formation or complex formation—i.e.,the acid/counter ion content of the nicotine salt, or thepolymeric/oligomeric material content of the nicotine complex, is notmeasured in the nicotine purity analysis. For example, a nicotinecomplex formed through complexation of a 99 wt. % pure nicotine material(99 wt. % nicotine free base+1 wt. % of impurities) with a polymer resinwould be considered herein to have a nicotine ‘purity’ of 99 wt. % eventhough the polymer resin would contribute significantly to constitutionof the nicotine complex. Purity of nicotine is determined using USPassay procedures, which may and often do, result in ‘purity’ over 100%as a result of inherent errors in the analysis (such as the case fornicotine purity determinations in nicotine polymer resin complexes whichmay inaccurately count weight contributions from the polymer resin to acertain degree). For example, particular mention is made of USP assayresults of between 98 wt. %-101 wt. %. For clarity purposes, applicantsconsider any USP assay result greater than 100% to be effectively 100%purity within the measurement accuracy of the assay.

Examples of potential impurities, such as those originating from thebiomass from which the nicotine is obtained (e.g., tobacco plant) orencountered during manufacture, include, but are not limited to,

-   -   tobacco related alkaloids such as cotinine, myosmine, anabasine,        β-nicotyrine, anatabine, nornicotine, nicotine-N-oxide,        isonicotine, neonicotine, N′-methyl anabasine, N′-methyl        anatabine, N′-methylmyosmine, nornicotyrine, 2,3′-bipyridyl, and        metanicotine;    -   plant matter such as tobacco leaf,    -   polyphenols such as rutin and quercetin;    -   biopolymers such as cellulose, lignin, pectin, starch, and        hemicellulose;    -   sugars such as sucrose, glucose, fructose,    -   polyacids acids such as malic acid, oxalic acid, and citric        acid;    -   pesticides such as alachlor, clomazone, metolachlor,        napropamide, pebulate, pendimethalin, sethoxydim, sulfentrazone        and aldicarb;    -   residual solvents such as 1,4-dioxane, 2-butanol,        2-ethoxyethanol, 1,2-dichloroethane, acetone, acetonitrile,        benzene, butane, cumene, cyclohexane, chloroform, ethanol, ethyl        acetate, ethyl benzene, ethylene oxide, ethylene glycol, ethyl        ether, heptane, isopropanol, methanol, methylene chloride,        hexanes, isopropyl acetate, pentanes, propane, toluene,        tetrahydrofuran, trichloroethene, and xylenes;    -   microbials;    -   heavy metals such as arsenic, cadmium, lead, chromium, and        nickel;    -   as well as mixtures thereof.

In some embodiments, the rapidly infusing composition is formulated witha form of nicotine which contains less than 1 wt. %, preferably lessthan 0.5 wt. %, preferably less than 0.1 wt. %, preferably less than0.05 wt. %, preferably less than 0.001 wt. %, preferably 0 wt. % of theabove listed impurities, based on a total weight of the nicotinematerial. In some embodiments, the rapidly infusing composition isformulated with a form of nicotine which contains no impurity, such asthose listed above, in an amount above the limits of detection (LOD)and/or limits of quantification (LOQ) for the technique/instrumentationbeing used to make such a determination. The purity of nicotine may bedetermined by methods known to those of ordinary skill in the art, forexample, one or more of liquid chromatography such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectrometry(LCMS), and liquid chromatography with tandem mass spectrometry(LCMSMS); gas chromatography such as headspace gas chromatography withflame ionization detection (HS-GC-FID), gas chromatography massspectrometry (GC/MS), and headspace gas chromatography-mass spectrometry(HSGCMS); inductively coupled plasma-mass spectrometry (ICP-MS); andpolymerase chain reaction (PCR).

To formulate the rapidly infusing compositions, nicotine may be providedin a variety of forms, such as nicotine free base, a nicotine salt, anicotine complex, mixtures thereof, solvates thereof, or any othersuitable form which is capable of releasing biologically active nicotineto provide the desired pharmacological action.

In some embodiments, nicotine may be provided in the form of a nicotinesalt. A single nicotine salt, or a mixture of nicotine salts may beprovided in the rapidly infusing composition. Any acid which provides apharmaceutically acceptable salt with nicotine may be used. Preferrednicotine salts are those resulting from complete ionization of nicotineand the acid. The nicotine salts may be formed from reaction of nicotinewith an inorganic acid or an organic acid, for example in a 1:1 to 3:1,or 2:1 molar ratio of acid to nicotine. The nicotine salts may beprepared under any conditions and using any techniques sufficient toform the salt, which are generally known to those skilled in the art,for example, U.S. Pat. Nos. 4,830,028, 9,738,622, U.S. Ser. No.10/556,880—each incorporated herein by reference in its entirety.

Examples of inorganic acids useful for forming the nicotine saltsherein, include, but are not limited to, hydrochloric acid, hydrobromicacid, hydroiodic acid, nitric acid, sulfuric acid, bisulfate salts suchas sodium bisulfate, sulfamic acid, phosphoric acid, and dihydrogenphosphate salts such as monosodium phosphate.

Examples of types of organic acids useful for forming the nicotine saltsherein, include, but are not limited to, aromatic acids (e.g., benzoicacids and substituted benzoic acids, naphthoic acids, etc.),hydroxyacids, heterocyclic acids, terpenoid acids, sugar acids (e.g.,pectic acids), amino acids, aliphatic acids and cycloaliphatic acids,dicarboxylic acids, keto acids, and sulfonic acids, with monocarboxylicacids being preferred. Suitable examples of organic acids include, butare not limited to, formic, acetic, propionic, isobutyric, butyric,alpha-methylbutyric, isovaleric, beta-methylvaleric, maleic, glutamic,benzoic, 2-acetoxybenzoic, 3,5-dihydroxybenzoic acid,2,3-dihydroxybenzoic, 4-acetamidobenzoic, gentisic, salicylic,sulfanilic, mucic, caproic, pamoic, 2-furoic, phenylacetic, heptanoic,octanoic, nonanoic, malic, citric, lactic, oxalic, malonic, glycolic,succinic, ascorbic, gluconic, tartaric, bitartaric, fumaric, pyruvicacids, levulinic, camphoric, benzenesulfonic, toluenesulfonic,methanesulfonic, ethanesulfonic, ethane disulfonic acid, and isethionicacids, as well as fatty acids (e.g., those having carbon chains of C₈ toC₂₀) such as stearic acid. Other useful organic compounds which exhibitan acid character and which form salts with nicotine may also be used,including phenolics such as guaiacol, vanillin, protocatechuic aldehyde,and the like.

Specific examples of nicotine salts suitable for use in the disclosedrapidly infusing compositions include, but are not limited to, nicotineacetate, nicotine monotartrate, nicotine bitartrate, nicotinehydrochloride, nicotine dihydrochloride, nicotine sulfate, and nicotinesalicylate.

In preferred embodiments, nicotine may be provided in the form of anicotine complex, where nicotine free base has been bound to (ionicallybound to), adsorbed to, absorbed into, or enclosed into a polymeric oroligomeric material, such as a starch, an alginate, a cyclodextrin(e.g., β-cyclodextrin), a cellulose, a polymer resin, or a combinationthereof, with particular preference given to a polymer resin. While theamount of nicotine (active) contained in the nicotine complex may vary,preferred nicotine complexes are those with a nicotine (active) contentof at least 5 wt. %, preferably at least 10 wt. %, preferably at least15 wt. %, preferably at least 20 wt. % and up to 60 wt. %, preferably upto 50 wt. %, preferably up to 45 wt. %, preferably up to 40 wt. %,preferably up to 35 wt. %, preferably up to 30 wt. %, preferably up to25 wt. %, based on a total amount of the nicotine complex. The amount ofnicotine complex used to formulate the rapidly infusing compositions maybe that amount which provides the desired active content of nicotine (asATI) as described heretofore.

Preferred nicotine complexes are nicotine polymer resin complexes,preferably those formed from complexation of nicotine with a cationexchange resin (thereby forming a nicotine cation exchange resincomplex). Suitable cation exchange resins are those which are stronglyacidic, weakly acidic, or of intermediate acidity, due to the presenceof acidic functionality, and are capable of forming an ionic complexwith nicotine which is stable and water insoluble. Once administered,the release of nicotine from the nicotine cation exchange resin complexoccurs through an ionic exchange process with counter ions available orthat become available through dissolution in the oral cavity. Thisresults in the release of free nicotine from the water insoluble polymerresin complexes, which is then ready for absorption through the oralmucosa.

Cation exchange resins suitable for forming nicotine cation exchangeresin complexes are generally those resins bearing acidic groups such ascarboxylic acids, sulfonic acids, phosphonic acids, phosphonous acids,iminodiacetic acids, and/or phenolic groups. While the cation exchangeresin can additionally possess anionic groups, the resin shouldnonetheless be overall acidic in nature for ionic complexation withnicotine. Useful cation exchange resins may include, but are not limitedto, methacrylic acid type polymers, acrylic acid type polymers, andpolystyrene type polymers with sulfonic acid and/or phosphonic acidfunctional groups. Particular preference is given herein to cationexchange resins where the acidic groups are bound to cross-linkedpolymers, such as those addition polymers formed from polymerization ofacidic monomers (e.g., acid functionalized styrene, methacrylic acid,and/or acrylic acid) with a crosslinking agent such as divinylbenzene.Other cation exchange resins are known, such as cross-linked phenolicresins, and other resins described in U.S. Pat. No.3,901,248-incorporated herein by reference in its entirety, which mayalso be used to form the nicotine cation exchange resin complexes. Aparticularly preferred example of a nicotine cation exchange resincomplex is nicotine polacrilex. Polacrilex (e.g., sold as AMBERLITEIRP64 from Dupont) is a weak carboxylic acid cross-linked polymer resinprepared from polymerization of methacrylic acid and divinylbenzene.

The rapidly infusing compositions may be formulated with a combinationof forms of nicotine, for example a combination of a nicotine salt and anicotine complex can be employed.

Preferred rapidly infusing compositions are those in which nicotine isprovided in a form that is a solid, for example, as a nicotine saltand/or a nicotine complex. Without being bound by theory, it is believedthat during the manufacture of the rapidly infusing composition, whenthe nicotine is presented in solid form, lyophilization from a drugproduct suspension generates a structured and robust matrix of gelatinas the water is removed via sublimation, and an even distribution of thesolid form of nicotine throughout the gelatin matrix. Such a structuredassembly of nicotine in solid form (e.g., nicotine salt and/or anicotine complex) suspended within a gelatin matrix is believed toafford the rapidly infusing composition with rapid disintegrationproperties and efficient transfer of nicotine from the hydrophilicvehicle to the mucous membrane of the buccal cavity, or the ventralsurface under the tongue, upon administration.

On the contrary, when the rapidly infusing composition is formulatedwith an oil form of nicotine (e.g., nicotine free base) duringmanufacture, lyophilization is instead performed from an o/w emulsion,which may produce a matrix of gelatin which is relatively unstable,disordered, and more prone to collapse back into an oil or semi-solidstate. The resulting composition tends to be less shelf stable, and canbe characterized by increased disintegration times, and modestdelivery/uptake of the nicotine into systemic circulation reflected inlonger onset times and overall less efficacy against nicotine withdrawalsymptoms.

In preferred embodiments, the rapidly infusing composition comprises,consists essentially of, or consists of gelatin, mannitol, sweetener,flavorant, and a nicotine cation exchange resin complex (e.g., nicotinepolacrilex). Nicotine cation exchange resin complexes, such as nicotinepolacrilex, increase mucosal uptake as compared to nicotine salts, suchas nicotine bitartate. This aids to achieve both the rapid uptake andefficient delivery of nicotine necessary to mimic the kinetics ofcigarettes.

Also contemplated for use as an active therapeutic ingredient arederivatives/analogs of nicotine that retain the desired pharmacologicalactivity of nicotine, such as the ability to stimulate dopamine release,that can be used for example in the treatment of nicotine withdrawalsymptoms and/or as an agent to help cessation of more harmful nicotinedelivery methods, including but not limited to smoking.Derivatives/analogs that retain substantially the same activity asnicotine, or more preferably exhibit improved activity, may be producedaccording to standard principles of medicinal chemistry, which are wellknown in the art. Such derivatives/analogs may exhibit a lesser degreeof activity than nicotine, so long as they retain sufficient activity tobe therapeutically effective. Derivatives/analogs may exhibitimprovements in other properties that are desirable in activetherapeutic agents such as, for example, improved solubility, reducedtoxicity, enhanced uptake, increased bioavailability, etc. Contemplatednicotine derivatives/analogs include, but are not limited to,nornicotine compounds (e.g., U.S. Pat. No. 5,776,957); lower N-alkylanalogs/derivatives of nicotine (e.g., U.S. Pat. No. 4,965,074);fluorinated or cyanonated nicotine compounds (e.g., U.S. Pat. No.5,278,176); unsaturated nicotine or anabasine compounds (e.g., U.S. Pat.No. 5,276,043); pyridylalklypiperidines or pyridylalkylpyrolidines(e.g., U.S. Pat. No. 5,214,060); gamma-nicotine compounds (e.g., U.S.Pat. No. 5,242,934); alpha-nicotine compounds (e.g., U.S. Pat. No.5,232,933); pyrrolidine substituted nicotine compounds (e.g., U.S. Pat.No. 4,442,292); pyridine substituted nicotine compounds (e.g., U.S. Pat.No. 4,321,387), as well as other compounds that can be used to treathabit disorders of the brain reward system, such as Lobelia alkaloids(e.g., lobeline, lobelanine, and lobelanidine) and those compoundsdisclosed in U.S. Pat. Nos. 5,223,497 and 4,966,916 each incorporatedherein by reference in its entirety.

It is contemplated that nicotine or derivatives/analogs of nicotine maybe useful in combination. It is also contemplated that nicotine orderivatives/analogs of nicotine may be useful in combination withcurrent Standards of Care for cessation of more harmful nicotinedelivery methods as well as any that evolve over the foreseeable future.Specific dosages and dosing regimens would be based on physicians'evolving knowledge and the general skill in the art.

In some preferred embodiments, nicotine or a derivative/analog thereofis the only active therapeutic ingredient in the rapidly infusingcomposition. In some preferred embodiments, nicotine is the only activetherapeutic ingredient in the rapidly infusing composition. In somepreferred embodiments, a nicotine derivative/analog is the only activetherapeutic ingredient in the rapidly infusing composition.

Process for Manufacturing the Rapidly Infusing Composition

Manufacturing of the rapidly infusing compositions may be accomplishedusing the RITe™ platform including generally by i) dissolving gelatinand mannitol and any other optional component of the pharmaceuticallyacceptable carrier and/or excipient system in water to form a solution,ii) adding the nicotine or analog to the solution and optionallymicronizing with a homogenizer to form a drug product suspension, andiii) lyophilizing the drug product suspension to remove water and formthe rapidly infusing composition.

One exemplary process is presented below, although it should beunderstood that numerous modifications and variations are possible, andthe rapidly infusing composition may be produced using processes ortechniques otherwise than as specifically described.

Purified water, gelatin, and sugar alcohol (e.g., mannitol) may becharged to a mixer, for example a pot equipped with an overhead stirrer,and heated (e.g., 40 to 80° C.) with agitation until complete solvation.Any desired sweetener (e.g., a mixture of sucralose and acesulfame-K)may then be added and allowed to dissolve.

Upon cooling, for example to 20 to 35° C., the solution may next betransferred to a homogenizer, and the ATI (e.g., nicotine in the form ofnicotine polacrilex) may be subsequently charged and dispersed using thehomogenizer, with optional micronization of the ATI, to form a drugproduct suspension. Any desired flavorant and colorant may be added atthis point with continued mixing. The drug product suspension may betransferred to a second mixer whilst maintaining a cooled temperature(e.g., 20 to 35° C.).

In a blistering machine equipped with a dosing system, blister pocketsmay next be filled with the drug product suspension until achieving atarget dose weight, followed by freezing in a suitable cryochamber. Theblister trays may be transferred from the cryochamber to a suitablerefrigerated storage cabinet (e.g., at a temperature below 0° C.) tokeep the product frozen prior to lyophilization. Then, the frozenblisters may be loaded into a lyophilizer and subject to lyophilizationto sublimate the water and form the rapidly infusing compositions.Finally, when the lyophilization cycle is deemed complete, final sealing(e.g., heat sealing of blister lidding) may be performed to provide therapidly infusing compositions in single dose units in individual blisterunits.

Therapeutic Applications and Methods

The present disclosure relates generally to methods of administeringnicotine or a pharmaceutically acceptable derivative/analog thereof to asubject in need thereof, whereby the nicotine or derivative/analogthereof is administered via the rapidly infusing composition of thepresent disclosure, in one or more of its embodiments. The methods maybe performed in order to provide a desired nicotine effect, to reduce auser's usage of more harmful nicotine delivery methods, to reduce auser's tobacco usage, to reduce a user's (non-tobacco) nicotine usage,to treat a user's nicotine withdrawal symptoms, and/or to reduce (andeventually overcome) a user's dependence on nicotine-containingproducts, or for any other purpose where nicotine administration may bedesirable. In preferred embodiments, the subject is a human.

In some embodiments, the methods herein are intended to provide a userwith a healthier alternative to smoking tobacco.

In preferred embodiments, the methods herein are used to manage asubject's nicotine withdrawal symptoms over the course of a nicotinecessation routine to aid the subject in quitting tobacco use or use of anon-tobacco-based nicotine product. The rapidly infusing compositions ofthe present disclosure are particularly useful as a tobacco replacementor as a means to reduce and/or stop tobacco use. The rapidly infusingcompositions of the present disclosure may be used as a totalreplacement of tobacco or other non-tobacco-based nicotine product(e.g., electronic cigarettes). Alternatively, the rapidly infusingcompositions of the present disclosure may be used as a partialreplacement of tobacco or other non-tobacco-based nicotine product(e.g., electronic cigarettes), and may be used concurrently with tobaccoor other non-tobacco-based nicotine product as part of a nicotinereduction program. For example, the rapidly infusing compositions areable to provide a user with rapid, on-the-spot relief from nicotinewithdrawal symptoms as needed during the course of a smoking cessationroutine involving a nicotine patch or some other smoking cessationtherapy.

Upon being administered buccally (between the cheek and gum) orsublingually (under the ventral surface of the tongue), the rapidlyinfusing composition preferably disintegrates in 5 seconds or less,preferably 4 seconds or less, preferably 3 seconds or less, preferably 2seconds or less, preferably about 1 second.

Owing to the rapid disintegration profile of the rapidly infusingcomposition and the direct introduction of ATI (e.g., nicotine) intosystemic circulation through the sublingual mucosa or the buccal mucosa,the methods described herein are particularly advantageous in terms oftheir ability to rapidly deliver nicotine or a derivative/analog thereofinto the user's bloodstream at high peak levels for receptor saturationand immediate relief of nicotine withdrawal symptoms, rivaling the onsettimes for pharmacological response provided by smoking tobacco.Administration of nicotine or related derivatives/analogs via the RITe™platform herein via the oral mucosae may provide such ATIs to the userat peak venous plasma levels of up to 50 ng/mL, for example at least 1ng/mL, preferably at least 5 ng/mL, preferably at least 10 ng/mL,preferably at least 15 ng/mL, preferably at least 20 ng/mL, preferablyat least 25 ng/mL, and up to 50 ng/mL, preferably up to 45 ng/mL,preferably up to 40 ng/mL, preferably up to 35 ng/mL, preferably up to30 ng/mL, which results in binding to the nicotinic acetylcholinereceptors (nAChRs) at 50% saturation or more, preferably 55% saturationor more, preferably 60% saturation or more, preferably 65% saturation ormore, preferably 70% saturation or more, preferably 75% saturation ormore, preferably 80% saturation or more, preferably 85% saturation ormore, preferably 90% saturation or more, preferably 95% saturation ormore, and up to 96% saturation, preferably up to 97% saturation,preferably up to 98% saturation, preferably up to 99% saturation. As aresult, the methods herein are particularly well-suited as a replacementto smoking tobacco or those seeking an aid to help them quit smoking.

With respect to administration, the rapidly infusing composition ispreferably administered to the subject via one or more of the oralmucosae, preferably via the buccal mucosa (buccally) or the sublingualmucosa (sublingually). Advantages of oral mucosal delivery include theease of administration, the ability to bypass first pass metabolicprocesses thereby enabling higher bioavailability than through enteraldelivery via the gastrointestinal tract, and extensive drug absorptionand rapid onset of therapeutic action due to either a large surface areain the case of sublingual administration or high-levels ofvascularization in the case of buccal administration.

Administration may be carried out by simply placing the rapidly infusingcomposition directly in the buccal cavity (between the cheek and gum) orover the sublingual mucous gland (under the ventral surface of thetongue). While the sublingual mucosa has a large surface area andextremely good permeability, the blood supply (blood flow) is lesserthan that of the buccal cavity. Furthermore, sublingual administrationtends to stimulate the flow of saliva more than buccal administration,and the increased saliva production may make it more difficult for usersto avoid swallowing. Any amount of ATI (e.g., nicotine) that isswallowed would be subject to first pass metabolism and thus overalllower bioavailability. Swallowing further results in greater variabilityin the effective amount of dosing, as a result of, including but notlimited to, the variability in the amount swallowed and the greater uservariability of bioavailability through first-pass metabolism for theamount swallowed. Therefore, in preferred embodiments, the rapidlyinfusing composition is administered buccally (through the buccalmucosa). The rapid disintegration of the rapidly infusing composition,approximately in 1-5 seconds in preferred embodiments, and buccaladministration together combine to provide optimal dosing control bylimiting the residence time in the oral cavity and ensuring that thevast majority of the nicotine or derivative/analog thereof is absorbedthrough the buccal mucosa.

Another particular advantage of the disclosed methods is thatbuccal/sublingual administration is not habit inducing when thecompositions, as here, disintegrate in a matter of seconds. For example,unlike other routes for administering nicotine such as smoking, chewing,dipping, snusing, sucking, etc., all of which are designed to behabitually performed by the user over prolonged periods of time, therapidly infusing compositions of the present disclosure are insteaddesigned to be placed in the buccal cavity or over the sublingual glandfor disintegration in a matter of seconds without mastication,deglutition, or any other neuromuscular activity. This ability toadminister ATIs such as nicotine in an easy-to-take format which isitself not associated with a habit-forming activity is particularlyadvantageous to those who desire to break a tobacco-related habit suchas smoking. As such, administration is intended to be mainly performedby the subject (psycho-stimulant self-administration), but may becarried out by someone other than the subject, for example, a healthcareprovider, family member, etc.

The actual amount of ATI administered to the subject may be varied so asto achieve the desired therapeutic response for a particular subject,composition, and mode of administration, without being toxic to thesubject. The selected amount of ATI administered to the subject willdepend upon a variety of factors including the activity of the ATIemployed, the route of administration, the time of administration, therate of excretion or metabolism of the particular compound beingemployed, the rate and extent of absorption, the duration of thetreatment, other drugs, compounds, and/or materials used in combinationwith the rapidly infusing composition, the age, sex, weight, condition,general health, the prior medical history of the subject, the subjectstolerance to stimulants such as nicotine, as well as like factors wellknown in the medical arts.

One having ordinary skill in the art can readily determine and prescribethe therapeutically effective amount of the rapidly infusing compositionrequired to provide the required amount of ATI. For example, dosing ofthe ATI (e.g., nicotine) could commence at levels lower than thatrequired in order to achieve the desired therapeutic effect andgradually increase the dosage until the desired effect is achieved. Ingeneral, a suitable dose of the ATI will be that amount which is thelowest dose effective to produce a therapeutic effect, which willgenerally depend upon the factors described above. Typically, when theATI is nicotine or a derivative/analog thereof, the therapeuticallyeffective amount of the rapidly infusing composition is that whichprovides nicotine or a derivative/analog thereof in a range from atleast 0.1 mg, preferably at least 0.2 mg, preferably at least 0.4 mg,preferably at least 0.6 mg, preferably at least 0.8 mg, preferably atleast 1 mg, preferably at least 1.2 mg, preferably at least 1.4 mg,preferably at least 1.6 mg, preferably at least 1.8 mg, preferably atleast 2 mg, and up to 10 mg, preferably up to 9 mg, preferably up to 8mg, preferably up to 7 mg, preferably up to 6.5 mg, preferably up to 6mg, preferably up to 5.5 mg, preferably up to 5 mg, preferably up to 4.5mg, preferably up to 4 mg per dose. In preferred embodiments, therapidly infusing composition is administered to the subject to provide 2to 4 mg of nicotine or derivative/analog thereof per dose (dosingevent).

Relative to subject body weight, the therapeutically effective amount ofthe rapidly infusing composition is that which provides nicotine or aderivative/analog thereof to the subject in an amount of at least 0.01mg/kg, preferably at least 0.015 mg/kg, preferably at least 0.02 mg/kg,preferably at least 0.025 mg/kg, preferably at least 0.03 mg/kg,preferably at least 0.035 mg/kg, preferably at least 0.04 mg/kg,preferably at least 0.045 mg/kg, preferably at least 0.05 mg/kg, and upto 0.15 mg/kg, preferably up to 0.13 mg/kg, preferably up to 0.11 mg/kg,preferably up to 0.1 mg/kg, preferably up to 0.09 mg/kg, preferably upto 0.08 mg/kg, preferably up to 0.07 mg/kg, preferably up to 0.06 mg/kg,per dose.

In order to achieve the above described therapeutically effective amountper dose, the methods herein may involve administering one, or more thanone, unit of the rapidly infusing composition per dose (dosing event).For example, in circumstances where each unit of the rapidly infusingcomposition contains 2 mg of ATI (e.g., nicotine), and it has beendetermined that the subject requires a therapeutically effective amountof 4 mg of ATI per dose, then the subject may be given two (2) units(e.g., tablets) to achieve the desired therapeutically effective amountof 4 mg ATI per dose. Accordingly, depending on the unit dose of ATI ineach unit of the rapidly infusing composition, the therapeuticallyeffective amount of ATI prescribed, etc., 1, 2, 3, 4, 5, or more units(e.g., tablets) may be administered to the subject per dose.Accordingly, the phrases “administering to the subject in need thereof,via the oral mucosa, a therapeutically effective amount of the rapidlyinfusing composition”, “the rapidly infusing composition isadministered”, etc., are intended herein to include administration of asingle unit (e.g., tablet), or multiple units (e.g., tablets), to thesubject in order to provide a therapeutically effective amount of ATI,e.g., nicotine. While it may be possible to administer partial (e.g.,half) tablets to the subject, for practical reasons, it is preferredthat one or more whole tablets are administered to the subject.

In many instances, a user may take the rapidly infusing composition ofthe present disclosure intermittently in response to an acute nicotinecraving. Thus in some embodiments, the rapidly infusing composition maybe administered simply ‘as needed’.

In other embodiments, the subject may be prescribed a dosage regimenthat involves multiple, separate dosing events at appropriate timeintervals throughout the day. In any case, the subject may beadministered a therapeutically effective amount of the rapidly infusingcomposition 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7times, 8 times, 9 times, 10 times, or even more times, optionally atappropriate intervals, throughout the day. The rapidly infusingcomposition may also be administered on an hourly dosing schedule (q),for example, administration may take place every 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours,as appropriate. Administration may be performed multiple times a day, onconsecutive days or otherwise, to achieve desired results (e.g., relieffrom nicotine withdrawal symptoms). For example, the subject may beadministered a therapeutically effective dose of the rapidly infusingcomposition, at least 1 time per day and up to 30 times per day, for 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 11 days, 12 days, 13 days, 14 days, or more, such as weeks,months, or even years.

Preferred dosing regimens for smoking cessation are those involving aconsistent dosing amount and schedule, with particularly preferreddosing schedules involving a gradual increase in time intervals betweendoses over the course of a multi-week program. For example, a subjectmay take buccally or sublingually a therapeutically effective dose ofthe rapidly infusing composition every 1 to 2 hours during an initialphase of a multi-week program, for example, for the first 1 to 6 weeks.The subject may also be provided instructions to take a minimum amountof the rapidly infusing composition in order to improve their chances ofquitting smoking, such as to take a minimum of 9 doses (e.g., tablets)of the rapidly infusing composition daily during this initial phase. Asubject may then take buccally or sublingually a therapeuticallyeffective dose of the rapidly infusing composition every 2 to 4 hoursduring an intermediate phase of the multi-week program, for example, forweeks 7 to 9. Finally, a subject may take buccally or sublingually atherapeutically effective dose of the rapidly infusing composition every4 to 8 hours during a final phase of the multi-week program, forexample, for weeks 10 to 12.

In some embodiments, the rapidly infusing compositions may beadministered (e.g., self-administered) at both predetermined intervalsas well as intermittently throughout the day to assist with cravingrelief. In one example, the subject may be provided with instructions totake a second dose (e.g., tablet) of the rapidly infusing compositionfor strong/frequent nicotine cravings within 1 hour from onset ofcraving symptoms, in addition to a consistent dosing schedule of amulti-week program, such as that described above.

The subject may also receive different dosages of nicotine orderivative/analog thereof commensurate with their pre-existing nicotinetolerance. For example, a user who smokes less than 25 cigarettes perday may initiate a multi-week smoking cessation program with the rapidlyinfusing composition having a relatively low single dose, such as 2 mgof nicotine per dose, while a user who smokes 25 or more cigarettes perday may initiate the multi-week smoking cessation program with therapidly infusing composition having a higher dose, such as 4 mg ofnicotine per dose. Upon completion of a multi-week smoking cessationprogram, the user may then optionally initiate another program cycleusing a lower dose of ATI than the program just completed (e.g., firstprogram using 4 mg nicotine, second program using 2 mg nicotine, etc.),until desired results, such as completely quitting smoking, areachieved.

When the ATI is nicotine, the maximum daily dosage of nicotine ispreferably no more than 100 mg, preferably no more than 90 mg,preferably no more than 80 mg, preferably no more than 70 mg, preferablyno more than 60 mg, preferably no more than 50 mg, preferably no morethan 40 mg, preferably no more than 30 mg, preferably no more than 20mg, preferably no more than 15 mg, preferably no more than 10 mg ofnicotine per day.

The RITe™ platform herein may be used as a stand-alone therapeutic agentfor administering nicotine or derivative/analog thereof, or may be usedin combination therapy—wherein the rapidly infusing composition is usedin combination with another nicotine-containing product, or one or moreother active therapeutic agents. The combination therapy may be appliedto treat nicotine withdrawal symptoms or a combination of nicotinewithdrawal symptoms and a different condition such as anxiety.

In some embodiments, the RITe™ platform of the present disclosure isadministered in combination with one or more other nicotine-containingproducts, such as a smoking tobacco product (e.g., cigarettes, cigars,and pipes), nicotine gum, a nicotine patch, a smokeless tobacco product(e.g., chewing tobacco, snuff, and snus), a non-tobacco-based nicotinepouch, a tobacco-smoke free inhaler (e.g., electronic cigarettes),nicotine lozenges, nicotine aerosols, etc. For example, a nicotine patchmay be used to supplement a smoking cessation program using the rapidlyinfusing compositions described herein, or vice versa.

In some embodiments, the RITe™ platform of the present disclosure isadministered in combination with one or more other active therapeuticagents for co-treatment of nicotine withdrawal symptoms and a conditionother than nicotine withdrawal, with specific mention being made todepression, anxiety, irritation of the respiratory tract, hypertension,dyspnea, inflammation, chronic sputum production, nausea, acid reflux,heartburn, and indigestion. Examples of such other active therapeuticingredients which may be co-administered with the rapidly infusingcompositions of the present disclosure include, but are not limited to,antidepressants and anxiolytics, such as selective serotonin reuptakeinhibitors (e.g., citalopram, escitalopram, fluoxetine, paroxetine,sertraline), serotonin and norepinephrine reuptake inhibitors (e.g.,duloxetine and venlafaxine), norepinephrine and dopamine reuptakeinhibitors (e.g., bupropion), tetracyclic antidepressants (e.g.,mirtazapine), combined reuptake inhibitors and receptor blockers (e.g.,trazodone, nefazodone, maprotiline), tricyclic antidepressants (e.g.,amitriptyline, amoxapine, desipramine, doxepin, imipramine,nortriptyline, protriptyline and trimipramine), monoamine oxidaseinhibitors (e.g., phenelzine, tranylcypromine, isocarboxazid,selegiline), benzodiazepines (e.g., lorazepam, clonazepam, alprazolam,and diazepam), serotonin 1A receptor agonists (e.g., buspirone,aripiprazole, quetiapine, tandospirone, and bifeprunox), andbeta-adrenergic receptor blockers (e.g., propranolol); expectorants suchas glycerol iodination products (e.g., domiodol and organidin) andpurinergic receptor agonists (e.g., uridine triphosphate and adenosinetriphosphate); anti-hypertensive agents including diuretics,beta-blockers, ACE inhibitors, angiotensin II receptor blockers, calciumchannel blockers, alpha blockers, alpha-2 receptor agonists, andcombined alpha and beta-blockers, with specific mention being made toamiloride; bronchodilators such as β₂-adrenergic agonists (e.g.,salbutamol and terbutaline), anticholinergics, and theophylline;anti-inflammatory agents such as oxicams, salicylates, acetic acidderivatives, fenamates, propionic acid derivatives,pyrazoles/pyrazolones, coxibs, and sulfonanilides; mucolytics (e.g.n-acetylcysteine, ambroxol, bromhexine, carbocisteine, erdosteine, andmecysteine); anti-nausea agents (e.g., ondansetron); and antacids (e.g.,magnesium oxide).

Combination therapy is intended to embrace administration of thesetherapies/products in a sequential manner, that is, wherein the rapidlyinfusing composition and one or more other therapies/products areadministered at a different time, as well as administration of thesetherapies/products, or at least two of the therapies/products, in asubstantially simultaneous manner. Substantially simultaneousadministration can be accomplished, for example, by administering to thesubject multiple, single dosage forms for each of the therapeuticagents. Sequential or substantially simultaneous administration of eachtherapeutic agent can be effected by any appropriate route including,but not limited to, oral routes, intravenous routes, transdermal routes,intramuscular routes, and direct absorption through mucous membranetissues. The therapeutic agents can be administered by the same route orby different routes. For example, the rapidly infusing compositionformulated with nicotine or a derivative/analog thereof may beadministered via buccal administration while a separate dosage form ofnicotine, for example a nicotine patch, may be administeredtransdermally. Alternatively, for example, the therapeutic agent(s) maybe administered buccally. Combination therapy also can embrace theadministration of the rapidly infusing composition in furthercombination with other non-drug therapies (e.g., supplemental oxygen).Where the combination therapy further comprises a non-drug treatment,the non-drug treatment may be conducted at any suitable time so long asa beneficial effect from the co-action of the combination of thetherapeutic agent(s) and non-drug treatment is achieved.

The examples below are intended to further illustrate the materials andmethods of the present disclosure, and are not intended to limit thescope of the claims.

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

As used herein the words “a” and “an” and the like carry the meaning of“one or more.”

The present disclosure also contemplates other embodiments “comprising”,“consisting of” and “consisting essentially of”, the embodiments orelements presented herein, whether explicitly set forth or not.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

Examples Rapidly Infusing Composition Ingredients

The ingredients that were used to make the rapidly infusing compositionare given in Table 1. USP=United States Pharmacopeia. EP=EuropeanPharmacopoeia. NF=National Formulary.

TABLE 1 Ingredients Ingredient Primary Function Specification GelatinMatrix former USP/EP/NF Mannitol Bulking agent USP/EP Orange flavorFlavorant Non-compendial Peppermint flavor Flavorant Non-compendialNicotine Polacrilex ATI USP/NF (20 wt. % active nicotine) SucraloseSweetener USP/NF Acesulfame-K Sweetener USP/NF Purified water VehicleUSP/EP

Example rapidly infusing compositions were made using the formulationsgiven in Tables 2 and 3. The amount of each component is expressed interms of weight percentage relative to a total weight (100%). The weightpercentage of each component in the drug product suspension is on a wetbasis (prior to removal of water). The weight percentage of eachcomponent in the rapidly infusing composition is on a dry basis (afterremoval of water).

TABLE 2 Example 1 rapidly infusing composition Drug product suspensionRapidly Infusing Composition % wt./wt. wt./unit % wt./wt. Ingredient(wet) (dry) (dry) Gelatin 3.5 10.5 mg 31 Mannitol 3 9 mg 26 Orangeflavor 0.4 1.2 mg 3.5 Peppermint flavor 0.4 1.2 mg 3.5 Nicotine 3.3 10mg (2.0 mg) 29 (5.8) Polacrilex (active) Sucralose 0.4 1.2 mg 3.5Acesulfame-K 0.4 1.2 mg 3.5 Purified water 88.6 Removed during Removedduring manufacture manufacture Total 100.0 — 100.0

TABLE 3 Example 2 rapidly infusing composition Drug product suspensionRapidly Infusing Composition % wt./wt. wt./unit % wt./wt. Ingredient(wet) (dry) (dry) Gelatin 3.5 10.5 mg 24 Mannitol 3 9 mg 20 Orangeflavor 0.4 1.2 mg 2.7 Peppermint flavor 0.4 1.2 mg 2.7 Nicotine 6.6 20mg (4.0 mg) 45.2 (9.0) Polacrilex (active) Sucralose 0.4 1.2 mg 2.7Acesulfame-K 0.4 1.2 mg 2.7 Purified water 85.3 Removed during Removedduring manufacture manufacture Total 100.0 — 100.0

Methods of Making the Rapidly Infusing Composition

-   -   Purified water was charged to a pot and mixed using an overhead        stirrer as an agitating device.    -   With agitation, the requisite amount of gelatin and mannitol        were dispersed, and the mixture was heated until the excipients        were dissolved.    -   Once dissolved, the sweeteners sucralose and acesulfame-K were        added and allowed to dissolve.    -   The solution was cooled to 30° C., moved to an overhead        homogenizer, and then the requisite amount of nicotine        polacrilex was charged and dispersed using the homogenizer to        create a drug product suspension.    -   The requisite amount of orange and peppermint flavor were        charged and mixed for 10 minutes.    -   The resulting drug product suspension was transferred to a        second overhead mixer and maintained at a temperature of 30° C.        for the ensuing dosing operation.    -   In a blistering machine equipped with a dosing system, blister        pockets were filled with a target dose weight of 300.0 mg of the        drug product suspension.    -   The product was frozen in a suitable cryochamber and then the        blister trays were transferred from the cryochamber to a        suitable refrigerated storage cabinet (temperature below 0° C.)        prior to lyophilizing to keep the product frozen.    -   The frozen blisters were loaded from the refrigerated storage        cabinet into lyophilizers and the product was lyophilized (water        was sublimated) to form the rapidly infusing compositions.    -   When the lyophilizing cycle was completed, the rapidly infusing        compositions were transferred from the lyophilizers to the        blistering machine where the blister trays were heat sealed with        lidding material. The resulting tablets are flat-topped circular        units approximately 15 mm in diameter with a convex bottom        packaged in individual blister units (see also U.S. Provisional        Application No. 63/114,181, filed Nov. 16, 2020—incorporated        herein by reference in its entirety).    -   The following tests were performed:        -   A seal integrity test was performed at −0.5 Bar for 30            seconds, 1-minute soak time        -   Visual inspection was performed        -   Dry weight testing was performed

1. A rapidly infused composition, comprising: a pharmaceuticallyacceptable binder and/or excipient system comprising gelatin andmannitol, and nicotine.
 2. The rapidly infusing composition of claim 1,which is lyophilized.
 3. The rapidly infusing composition of claim 1,which has a disintegration time of approximately 1 to 30 seconds indeionized water maintained at 37° C.±2° C.
 4. The rapidly infusingcomposition of claim 1, which has a disintegration time of approximately1 to 5 seconds in deionized water maintained at 37° C.±2° C.
 5. Therapidly infusing composition of claim 1, wherein the gelatin is presentin the rapidly infusing composition in an amount of 10 to 35 wt. %,based on a total weight of the rapidly infusing composition on a drybasis.
 6. The rapidly infusing composition of claim 1, wherein thegelatin is mammalian gelatin.
 7. The rapidly infusing composition ofclaim 6, wherein the mammalian gelatin is bovine gelatin.
 8. The rapidlyinfusing composition of claim 1, wherein the mannitol is present in therapidly infusing composition in an amount of 5 to 35 wt. %, based on atotal weight of the rapidly infusing composition on a dry basis.
 9. Therapidly infusing composition of claim 1, wherein the nicotine is presentin the rapidly infusing composition in an amount of 0.1 to 25 wt. %,based on a total weight of the rapidly infusing composition on a drybasis.
 10. The rapidly infusing composition of claim 1, wherein thenicotine is provided in the form of a nicotine salt or a nicotinecomplex.
 11. The rapidly infusing composition of claim 10, wherein thenicotine is provided in the form of the nicotine complex.
 12. Therapidly infusing composition of claim 11, wherein the nicotine complexis a nicotine cation exchange resin complex.
 13. The rapidly infusingcomposition of claim 12, wherein the nicotine cation exchange resincomplex is nicotine polacrilex.
 14. The rapidly infusing composition ofclaim 1, wherein the nicotine has a purity between 95 and 100% by weighton a basis of nicotine free base.
 15. The rapidly infusing compositionof claim 1, which is formulated with a solid form of nicotine.
 16. Therapidly infusing composition of claim 1, wherein the rapidly infusingcomposition further comprises at least one selected from the groupconsisting of a sweetener, a flavorant, and a colorant.
 17. The rapidlyinfusing composition of claim 16, wherein the rapidly infusingcomposition comprises the flavorant, and the flavorant comprises amixture of orange flavor and peppermint flavor.
 18. The rapidly infusingcomposition of claim 16, wherein the rapidly infusing compositioncomprises the sweetener, and the sweetener comprises a mixture ofsucralose and acesulfame-K.
 19. A process for manufacturing the rapidlyinfusing composition of claim 1, comprising: dissolving gelatin andmannitol in water to form a solution; adding the nicotine to thesolution to form a drug product suspension; and lyophilizing the drugproduct suspension to remove water and form the rapidly infusingcomposition.
 20. A method of administering nicotine to a subject,comprising administering to the subject in need thereof, via the oralmucosa, a therapeutically effective amount of the rapidly infusingcomposition of claim
 1. 21. The method of claim 20, wherein the rapidlyinfusing composition is administered buccally to the subject via thebuccal mucosa.
 22. The method of claim 20, wherein the therapeuticallyeffective amount of the rapidly infusing composition is that whichprovides from 0.1 to 10 mg of nicotine per dose.
 23. The method of claim20, wherein the rapidly infusing composition is administered to thesubject 1 to 10 times per day.
 24. The method of claim 20, wherein thesubject is a human.
 25. A method of reducing a subject's usage of moreharmful nicotine delivery methods, comprising administering to thesubject in need thereof, via the oral mucosa, a therapeuticallyeffective amount of the rapidly infusing composition of claim
 1. 26. Themethod of claim 25, wherein the rapidly infusing composition isadministered buccally to the subject via the buccal mucosa.
 27. Themethod of claim 25, wherein the therapeutically effective amount of therapidly infusing composition is that which provides from 0.1 to 10 mg ofnicotine per dose.
 28. The method of claim 25, wherein the rapidlyinfusing composition is administered to the subject 1 to 10 times perday.
 29. The method of claim 25, wherein the subject is a human.
 30. Amethod of reducing nicotine withdrawal symptoms in a subject, comprisingadministering to the subject in need thereof, via the oral mucosa, atherapeutically effective amount of the rapidly infusing composition ofclaim
 1. 31. The method of claim 30, wherein the rapidly infusingcomposition is administered buccally to the subject via the buccalmucosa.
 32. The method of claim 30, wherein the therapeuticallyeffective amount of the rapidly infusing composition is that whichprovides from 0.1 to 10 mg of nicotine per dose.
 33. The method of claim30, wherein the rapidly infusing composition is administered to thesubject 1 to 10 times per day.
 34. The method of claim 30, wherein thesubject is a human.